A PRACTICAL HANDBOOK
OF DUTIES AND RESPONSIBILITIES
FOR THE OFFICERS OF
THE CARCINOGENESIS SPECIALTY SECTION
Upon
being elected as an officer of the Carcinogenesis Specialty Section
(CSS) the first question one asks is “So, what am I supposed to do?.
Details of the rules and regulations pertaining the CSS can be found
in the by-laws on file with the Society of Toxicology (SOT). This
handbook, however, is a practical guide put together by a number of
past and current officers. It contains duties, timetables, examples,
and helpful hints. Please add to it and pass it on to the succeeding
officers. This handbook is dedicated to those people willing to
devote their time to the success of this dynamic Specialty Section.
Updated March 13, 2002 by Byron Butterworth
Past President
Elections
Lead
the nominating committee for new officers. Work with the current
presidency and councilors for suggestions. The one-year term officer
elected every time is the Vice President Elect. Two-year term
officers include the Secretary/Treasurer and the councilors. The
ballots should go out in early January. So, the legwork should
be done in December. Candidates must be members of the CSS.
After agreeing on the best list, the Past President will contact each
potential candidate to see if they will agree to run.
The
Past President will then coordinate with the President and Secretary/Treasures
to convey the final list of candidates to the SOT Headquarters.
For example, the contact person in 2002 at SOT was Ms. Rita Rose.
SOT then sends out the ballots via e-mail. Members vote via return
e-mail. SOT then informs the President of the results, who informs
the winners and thanks all who ran.
Annual Council Meeting
Attend
the annual CSS council meeting at the SOT Annual Meeting.
President
Elections
Work
with the Past President to put together a slate of candidates and hold
the election in January (see Past President).
Newsletter
Work
with the Secretary/Treasurer to issue at least two issues of the CSS
newsletter. A President’s message is always included (see Appendix
for an example of a newsletter). It is always a good idea to have
the Secretary/Treasurer review the Presidents message. The newsletter
should inform the Section members about activities and contain reminders
about deadlines such as submission of student awards and requests for
suggestions for symposia. Solicit short informative articles from
the membership on their research and emerging issues.
Preparations for the Annual Meeting
As
the annual meeting approaches, SOT Headquarters will contact the President
regarding CSS meetings to be held. There are generally two.
The first is the CSS Reception. SOT will help set dates and times.
A form needs to be filled out requesting room size, microphone on podium,
and choice of food. The second meeting is the CSS council meeting.
It often makes sense to schedule that meeting in the same room as the
reception, but a couple of hours earlier. A form also needs to
be filled out for any tables, food, or AV equipment for that meeting.
Annual Council Meeting
Preside
at the annual CSS council meeting at the SOT Annual Meeting. Present
the results of the elections and student awards. Discuss any Specialty
Section Business.
Annual Report
SOT
Headquarters asks for an Annual Report in May from the Specialty Section.
The request goes to the President, but is really something that is best
done with the Secretary/Treasurer. Working together means that
items are not likely to be left out. An example of an Annual Report
is in the Appendix.
Budget
SOT
Headquarters sends the President a CSS Budget summary. It contains
Net Assets allocated by SOT and expenses toward those assets.
Since SOT is in control of most items, there is little to do but watch
the bottom line. The Secretary/Treasurer should be kept in the
loop. Expenses are generally for plaques and checks for the Student
Awards and for food for the Reception. Symposia speakers who are
SOT members pay their own way. Guest speakers sponsored by the
CSS have their travel paid. So, that is one expense to watch.
However, lately the SOT has taken over the guest travel in their budget,
rather than charge it to the individual specialty sections. Keep
up to date on the current policy.
CSS Sponsored Symposia, Workshops,
and Continuing Education Courses
At
the annual meeting the CSS sponsors symposia, workshops, and continuing
education courses. The Vice President and President are responsible
for soliciting suggestions from the CSS membership and submitting them
to the SOT Program Committee (see Vice President).
The
President of the CSS writes a letter of sponsorship that is sent
to the SOT Headquarters to support each proposed program. Any
specific symposium may have the sponsorship of more than one Specialty
Section. The President will spend some time on the phone and via
e-mail with presidents of the other Specialty Sections asking for, and
being asked for sponsorship. The President then writes the appropriate
letters of sponsorship to the SOT Headquarters. This can be done
via attachments to e-mail.
Workshops and Special Meetings
The
CSS may during the course of the year sponsor a special workshop or
scientific meeting. This requires a great deal of extra effort
on the part of the organizer. People have been so overwhelmed
with work that no volunteers have come forward for the past few years.
Sponsoring such a meeting is laudable, if one can find those willing
to put in the effort. This activity is optional and is generally
proportional to the enthusiasm of the current officers.
CSS Reception
The
CSS Reception is held in conjunction with the SOT Annual Meeting.
The President presides at this meeting. The order of business
is generally as follows:
Welcome Message - President
Announcement of Election Results - President
Presentation of Student Awards - Vice
President
Solicitation for Symposia and Continuing
Education Courses - Vice-President Elect
Introduction of incoming President (current
VP) - President
Wrap-up and thank you to outgoing President
and officers including presentation of a plaque to the outgoing President
- Vice President
Vice President
CSS Sponsored Symposia, Workshops,
and Continuing Education Courses
At
the annual meeting the CSS sponsors symposia, workshops, and continuing
education courses. The Vice President and President are responsible
for soliciting suggestions from the CSS membership and submitting them
to the SOT Program Committee. Members of the CSS are involved
in cutting-edge research and we want to share that excitement with our
fellow SOT members. Organizing a symposium that includes one’s
research is informative for the SOT membership and prestigious for the
research scientist.
Because
everyone is so overcommitted, it often requires encouragement to get
an individual to put together and chair a symposium or continuing education
course. The Vice President and President should identify important
advances in the field and contact those individuals who may be willing
to put a program together. the President and Vice President should
provide guidance to those who are willing to organize a symposium or
course. Look at the current Program Book for guidance as to types
of programs, number of speakers, organization, etc. Usually an
introduction with 4 speakers is about right for a symposium. Be
sure to be a resource and work closely with the organizers, so that
they don’t go astray in formulating their programs. Often you
will be pleasantly surprised and someone will come forward with a great
suggestion with speakers already contacted.
The
person putting together the program usually serves as the chairperson.
Symposia organizers and chairpersons MUST be SOT members
- no exceptions. He or she comes up with a list of speakers and
topics and makes sure that those individuals are willing to make the
commitment to speak. Those speakers should be told up front by
the organizing person that this is a proposed program.
The programs are submitted in April to the SOT Program committee on
the official form.
NOTE
- If the Program Committee does not approve of the symposium, it
dies. This can be a serious problem that results in frustration
and hurt feelings. Individuals can put in a lot of work that comes
to nothing. Then they have to call each speaker and tell them
the bad news. SOT should re-think the process, but for now, it
is how things are done. Be prepared to be sympathetic and to use
your anger management skills. For example, in 2001 we had several
excellent symposia that were not accepted by the program committee.
It was a less than pleasant situation.
Note
that the submissions for symposia are due in April. That means
that the incoming Vice President and President have to get to work to
line up organizers, chairpersons, and symposia months before that.
If you wait till the March SOT Annual Meeting, you will have your backs
to the wall.
Student Awards
The
Vice President is responsible for the student awards. Students
represent the future of the CSS. The Student Awards provide encouragement
and incentive for their participation. The students are recognized
at the CSS reception at the annual meeting. The winners receive
recognition plaques and monetary awards for 1st ($500), 2nd ($300),
and 3rd ($100) place. Application involves submission of the meeting
abstract and a letter of sponsorship from the graduate student advisor.
Abstracts should be submitted by December 1 to the current Vice President.
The announcement of the student award competition should be made early
in the fall by both SOT Headquarters (see announcement in the Appendix)
as well as in the newsletter.
The
applications are judged by a committee made up of the Vice President
and the CSS Councilors. After the judging, each winner is informed
by the Vice President. Informing the winners is important, to
make sure that they are present at the CSS reception. The Vice
President fills out the RECOGNITION ORDER FORM that goes to the SOT
Headquarters. For example, in 2002 that contact was Ms. Rita Rose.
That form lists the winners and is the means of ordering 1) The certificates;
2) The plaques; and 3) The award checks. The Vice President
picks up all this material from the SOT Headquarters at the annual meeting.
The certificates should be given right away so that they can be displayed
on the poster. You may also want to attach a blue, red, or white
ribbon, if you wish. If a winning student is giving a talk, the
fact that they are a winner should be announced by the Chairperson of
the session. The plaques and checks are awarded by the Vice President
at the CSS reception. See the Appendix for an example of the letter
to an award winner.
Plaque for the Outgoing President
Beginning
in 2001 we felt that it was appropriate and thoughtful that the outgoing
President receive a plaque from the Specialty Section expressing appreciation
for his or her service. The Vice president should have a plaque
made up and charge the cost to the Specialty Section. A modest
plaque of about 8 x 10 inches or so is all that is needed. The
plaque is awarded by the Vice President at the CSS Reception.
Annual Council Meeting
Attend
the annual CSS council meeting at the SOT Annual Meeting.
Vice President Elect
CSS Sponsored Symposia, Workshops,
and Continuing Education Courses
At
the annual meeting the CSS sponsors symposia, workshops, and continuing
education courses. The Vice President and President are responsible
for soliciting suggestions from the CSS membership and submitting them
to the SOT Program Committee (see Vice President).
Note
that the submissions for symposia are due in April. That means
that the Vice President and President have to get to work to line up
organizers, chairpersons, and symposia months before that. If
you wait till the March SOT Annual Meeting, you will have your backs
to the wall. So, as Vice President Elect, you will become Vice
President at the Annual Meeting in March. You need to begin working
before that with the President-to-be to line up symposia and continuing
education courses.
Annual Council Meeting
Attend
the annual CSS council meeting at the SOT Annual Meeting.
Secretary/Treasurer
Elections
Work
with the Past President to put together a slate of candidates and hold
the election in January (see Past President).
Budget
SOT
Headquarters sends the President a CSS Budget summary. It contains
Net Assets allocated by SOT and expenses toward those assets.
Since SOT is in control of most items, there is little to do but watch
the bottom line. The Secretary/Treasurer should be kept in the
loop. Expenses are generally for plaques and checks for the Student
Awards and for food for the Reception. Symposia speakers who are
SOT members pay their own way. Guest speakers sponsored by the
CSS have their travel paid. So, that is one expense to watch.
However, lately the SOT has taken over the guest travel in their budget,
rather than charge it to the individual specialty sections. Keep
up to date on the current policy.
Newsletter
Work
with the President to produce at least two issues of the CSS newsletter
(see President and example in the Appendix).
Annual Council Meeting
Attend
the annual CSS council meeting at the SOT Annual Meeting.
Councilor
Elections
Serve
as a resource for the Past President to help put together a slate of
candidates for the election in January (see Past President).
Student Awards
Serve
on the student awards judging committee headed by the Vice President
(see Vice President). Visit each winning student presentation,
introduce yourself as a Council Member and let them know we appreciate
their participation.
CSS Sponsored Symposia, Workshops,
and Continuing Education Courses
At
the annual meeting the CSS sponsors symposia, workshops, and continuing
education courses. Encourage the membership to take the responsibility
for such a program (see Vice President).
Newsletter
Encourage
the membership to submit articles for the Newsletter (see Secretary/Treasurer)
Annual Council Meeting
Attend
the annual CSS council meeting at the SOT Annual Meeting.
APPENDIX
Example Announcement for the Student
Awards to be sent out by SOT Headquarters
2002 Student Awards
Information for the Carcinogenesis Specialty Section of the Society
of Toxicology
Specialty Section: Carcinogenesis
Award Requirement: Submit abstract and
letter of sponsorship from graduate student advisor.
Areas of Research: Carcinogenesis
Deadline: December 1, 2001
Contact: (Obviously, use current
Vice President) Dr. Samuel Cohen, University of Nebraska Medical
Center, Pathology/Microbiology, 983135 Nebraska Medical Center, Omaha,
NE 68198-3135, phone: (402) 559-6388, e-mail: scohen@unmc.edu
Winner Receives: Recognition plaques
and monetary awards to 1st ($500), 2nd ($300), and 3rd ($100) place
winners
Example of the letter informing the
student award winners
Dear Ms. Auyeung:
On
behalf of President Byron E. Butterworth, the judging committee and
myself, it is my pleasure to inform you that you have won first place
in the Student Awards Competition of the Carcinogenesis Specialty Section
of the Society of Toxicology for 2002. Your abstract, “The AH
Receptor and AH Receptor Nuclear Translocator Mediates Stimulation by
Oltipraz of the Xenobiotic Response Element in the Rat UGT1A6 Gene,”
was excellent and clearly describes research of the highest quality.
Your mentor, Dr. Joe Ritter, was very supportive and I am sure is pleased
and proud of your accomplishment.
The
first place award consists of a check for $500, a plaque, and a ribbon
for your poster. These will be presented to you at our reception
for the Carcinogenesis Specialty Section at the annual meeting of the
Society of Toxicology in Nashville, March 20, 2002.
Please
let me know if you have any questions. Again, congratulations
on a job well done.
Sincerely yours,
Samuel M. Cohen, M.D., Ph.D.
Vice President and “Chair of the Judging Committee
Carcinogenesis Specialty Section
copy:Dr. Joe Ritter
Dr.
Byron Butterworth
Example of and Annual Report
Carcinogenesis Specialty Section Annual
Report : 2000-2001
I. Introduction
2000-20012001-2002
PresidentYvonne DraganByron Butterworth
Vice PresidentByron ButterworthSam Cohen
Vice President ElectSam CohenJon Cook
Secretary/TreasurerJennifer CountsJennifer
Counts
CouncilorsDavid WarshawskyJane Allen
Jane
AllenHoward Glauert
Karen Steinmetz
Past PresidentJames YagerYvonne Dragan
2000-2001 Annual Meeting Date: March
26, 2001
II. Activities
The
Carcinogenesis Specialty Section Annual Meeting was held on March 26,
2001 in San Francisco in association with the Society of Toxicology
Annual Meeting. Approximately 30 people were in attendance.
President Yvonne Dragan led the meeting. She reviewed the goals
of the Specialty Section, introduced the winners of the election, and
noted business items of importance. Sam Cohen reminded those interested
in proposing a Symposium or Continuing Education course for 2002 to
get that information to him by the April deadline. Byron Butterworth
presented the Student Presentation Awards, discussed future goals, and
recognized Yvonne Dragan for her dedicated service.
Student Award Winners Were
First Place: Jennifer L. Ariazi
Immature Rat Mammary Epithelial Cells
(RMECs) are More Susceptible than Mature RMECs to the Cytolethal, Carcinogenic,
and Mutagenic Effects of N-Nitroso-N-Methylurea
McArdle Laboratory for Cancer Research
University of Wisconsin, Madison
Second Place: Tasha R. Smith
Amino Acid Substitution Variants of
APE1 and XRCC1 Genes Associated with Ionizing Radiation Sensitivity
Department of Cancer Biology
Wake Forest School of Medicine
Third Place: Angela Siesky
Modulation of Hepatic Cell proliferation
and Oxidative Stress in 2-Butoxyethanol Treated Mice
Department of Pharmacology and Toxicology
Indiana University School of Medicine
III. Financial Report
Balance as of 7/1/2000
Revenue from Dues
Non-dues Revenue
Expenses
Balance as of 6/30/01
IV. Future Plans
2002 Symposia and Continuing Education
Courses Proposed by Members of and Sponsored by the Carcinogenesis Specialty
Section are as follows:
Symposia
Scientific Basis for Reducing Harm from
Cigarette Smoking
The Status of Toxicogenomics in Toxicology
Rodent Models of Endocrine Neoplasia:
Are they Relevant to Human Risk Assessment
Carcinogens Exhibit Thresholds: The Value
of Mechanistic Studies
Continuing Education Course
Internal Dosimetry: Measurement of DNA
Damage as and Indicator of Internal Exposure to Genotoxicants
Sample Newsletter
Carcinogenesis Specialty
Section
of the Society of Toxicology
NewsletterSeptember 2001
President’s Message
Dear Specialty Section Members:
I
am writing this message saddened by the recent loss of life of so many
innocent victims at the hands of terrorists. I know that we all
send our deepest sympathies to those who have lost family or friends
in those senseless acts. Compassion, knowledge and wisdom have
formidable enemies in hatred, ignorance, and superstition. Acts
of destruction are easy, the processes of learning and creation are
difficult. I reflect on the numbers of people who have dedicated
their careers to understanding, preventing, and curing cancer and ministering
to those afflicted. Progress has come as a result of an ever-growing
knowledge base passed from generation to generation. We are fortunate
to be able to contribute at a time when information and the tools for
learning are so great. We are privileged, and somewhat sheltered,
to be able to work within a world-wide community of scientists where
compassion, knowledge and wisdom are, indeed, paramount. However
you are choosing to cope with the sorrow, may your efforts help in achieving
the peace longed for by so many.
Don’t
forget that the deadline for the electronic submission of abstracts
for the Annual Meeting of the Society of Toxicology is October 1, 2001.
Members of the Carcinogenesis Specialty Section (CSS) have always provided
a major contribution to the Meeting and I am sure that this tradition
will continue. One of the most important activities of our members
is the training of students. These individuals represent the future
of our discipline and we need to encourage their participation.
The Student Awards of the CSS provide a great way of doing this.
The students are recognized at the CSS Reception at the annual meeting.
The winners receive recognition plaques and monetary awards for 1st
($500), 2nd ($300), and 3rd ($100) place. Application is simple
and requires only submission of the meeting abstract and a letter of
sponsorship from the graduate student advisor. For the Student
Awards: abstracts should be submitted by
December 1, 2001 to Dr. Samuel Cohen, University of
Nebraska Medical Center, Pathology/Microbiology, 983135 Nebraska Medical
Center, Omaha, NE 68198-3135. As Vice President, Dr. Cohen
is responsible for the judging this year. Our students are dedicated
and energetic. Participation in the awards competition provides
recognition and a spirit of community.
Remember
also that it is not too early to begin to think of topics for symposia
and continuing education for the next annual meeting. Myself or any
of the other CSS officers will be glad to discuss your ideas or any
suggestions you might have to improve our organization. The CSS
officers this year are: President - Byron Butterworth, Vice President
- Sam Cohen, Vice President-Elect - Jon Cook, Secretary/Treasurer -
Jennifer Counts, Councilors - Jane Allen, Howard Glauert, and Karen
Steinmetz, Past-President - Yvonne Dragan. The success of the
Society and the CSS is, of course, only a reflection of your efforts.
Thank you for your involvement and support.
Sincerely,
Byron E. Butterworth
President
As Always
– Please Submit Articles for the CSS Newsletter
Please send Jennifer Counts articles
and information for inclusion in the CSS newsletters (counts.jl@pg.com
or by phone 513-626-0023). Your continued support will ensure
that this remains an excellent specialty section.
Guest Article
The Use of Animal
Models for the Study of Breast Cancer
Michelle Bennett
Livermore National Labs
Of
the approximately 180,000 cases of breast cancer that are diagnosed
among women this year, 7% can be attributed to the genetic inheritance
of mutations in breast cancer susceptibility genes. Seventy percent
of breast cancer is believed to arise as the result of a combination
of genetic factors and environmental exposures. Epidemiologic studies
provide evidence that environmental factors, alone or in combination
with genetic factors influence breast cancer development in women. Hormone
replacement therapy (HRT) is associated with an increased risk for breast
cancer in postmenopausal women (1,2). HRT increases mammographic breast
density, a risk factor for breast cancer, by inducing ductal growth
and proliferation (3). High birth weight, likely influenced by hormonal
exposures in utero, was identified as a risk factor for breast cancer
development (4). Observations like these have focused attention on the
timing of exposure as a critical risk factor for breast cancer development.
In addition, the effects of endogenous or exogenous factors, such as
oral contraceptives, pregnancy and smoking, are being studied in high-risk
populations such as BRCA1 and BRCA2 mutation carriers. Such studies
provide information about gene-environment interactions which may be
useful for making science-based recommendations about lifestyle choices
that influence breast cancer risk (5-7).
Whereas
epidemiologic studies are necessary and of immense value, model systems
can be used to elucidate health outcomes from exposures and to define
their mechanisms of action. Animal models provide a means for examining
the effect of environment on breast cancer development alone or in combination
with variables such as genetic alterations and timing or frequency of
exposure. The genetic alterations that are most commonly studied rodent
models include the gain of function mutations (oncogene activation)
that can be studied in transgenic animals, and the loss of function
mutations (tumor-suppressor gene inactivation) which are typically evaluated
in mice with genes altered by gene-targeting and homologous recombination
or mutagenesis techniques. Carcinogen treated rat models have been used
extensively to define the consequences of single chemical exposures
during different periods of mammary gland growth and development. The
use of rodent systems permits an exposure to be specifically tested
in the context of all organ systems, a critical consideration given
one chemical can have dramatically different organ-specific effects.
In addition, these models enable investigations into exposure effects,
elucidate the mechanisms which alter risk to breast cancer, make predictions
about human relevance, and provide preliminary data and rationale for
the testing of putative therapeutics or preventative treatments for
breast cancer.
Mammary Gland Development
Susceptibility
to environmental exposures may be more complex in the mammary gland
because its development occurs in multiple stages. Fetal development
of the mammary gland rudiment is governed by tissue interactions in
both males and females. In females, the onset of ovarian function during
puberty drives morphogenesis such that the mammary ducts elongate and
branch into the surrounding stroma. This burst of proliferation ceases
when the mammary ducts reach the limits of the fat pad. Massive differentiation
of the mammary gland, triggered by pregnancy, results in lobulo-alveolar
development, culminating in milk-producing structures at parturition.
After weaning involution takes place and is characterized by massive
apoptosis. The evaluation of the mammary gland in a whole animal systems
presents a powerful opportunity to evaluate the consequences of genetic
and environmental factors on normal mammary gland growth and differentiation,
non-neoplastic changes, and progression to neoplasia as they relate
to the timing of exposure and the development of the mammary gland.
Rodent Models for the Study of Breast
Cancer
The
carcinogenic process from an initiating event to tumor promotion and
development is widely accepted to result from the accumulation of mutational
events. The identification of the genes in which these mutations arise
during promotion and progression largely include proto-oncogene and
tumor suppressor genes. Numerous transgenic and gene-deficient mice
have been developed to model different aspects of breast cancer. Rats
and mice are also used to understand better the consequences of exposure
to agents suspected of causing and/or preventing mammary tumor induction
by chemical treatment. The following sections will describe three commonly
used systems in which to model human breast neoplasia. The following
paragraphs represent a small sampling of the many models currently available.
Transgenic Mouse Models
There
are two complementary transgenic mouse models in which to study the
consequences of Her-2/Neu oncogene activation. The models are relevant
to human cancer because patients whose breast tumors overexpress Her-2/Neu
have reduced survival and an increased risk of metastasis compared to
patients whose tumors do not. Approximately 30% of breast tumors overexpress
the Her-2/Neu oncogene.
The
mouse models that include the MMTV-neu transgenic mouse, which
harbors a mutated form of the neu gene under the control of the
mouse mammary tumor virus (MMTV) promoter (8), and MMTV/wild-type neu
mice, that harbor the neu proto-oncogene under the control of
the MMTV promoter (9). The MMTV-neu transgenic mice develop mammary
tumors with an incidence of 70% by 21 weeks of age, which varies depending
on diet (10). At eight weeks of age these mice have multiple hyperplastic
and dysplasic nodules in their mammary glands which progress to form
mammary adenocarcinomas, and are histologically similar to human comedocarcinomas
(reviewed in (11)). The strong evidence supporting the view that the
overexpression of c-neu played a role in breast cancer development
led to the creation of MMTV/wild-type neu
mice. This mouse model develops focal mammary adenocarcinomas surrounded
by hyperplastic mammary epithelium by seven months of age with frequent
metastasis to the lung (9). Molecular analysis of the tumors revealed
that the neu transgene had been mutated resulting in constitutive
expression (reviewed in (12)).
The
dysregulation of cyclins, proteins that activate cyclin-dependent kinases
to regulate progression through the cell cycle, has been associated
with breast cancer development in women. In particular, cyclins D1
and E have been reported to be overexpressed in human breast
cancer cell lines and tumor samples (13-15). Transgenic mice have been
generated to model overexpression of both cyclin D1 and E.
MMTV/cyclin D1 mice are characterized by the development of lobulo-alveolar
structures in the mammary gland after sexual maturity and mammary adenocarcinomas
by 18 months of age (16). Transgenic mice overexpressing cyclin E
under the control of the -lactoglobulin (BLG) promoter have also
been characterized (17). In general, BLG/cyclin E mice develop
transient hyperplastic mammary glands while they are lactating and develop
mammary tumors with about 12% incidence.
Scatter
factor (SF), also known as hepatocyte growth factor (HGF) and designated
HGF/SF, plays a role in mammary gland ductal morphogenesis by inducing
branching of the ducts (18). HGF/SF is produced in the stromal tissue
surrounding the mammary ducts and binds to the c-Met receptor expressed
by the epithelial cells. HGF/SF and c-Met accumulate in breast tumors
and is associated with metastatic characteristics (19-21). Two transgenic
mouse strains have been described that express an activated form of
the Met oncogene under the control of the metallothionein promoter (22,23).
In one instance, the mice develop hyperplastic nodules that progress
to mammary tumors by 14 months of age, in addition to tumors at other
sites (22), while in the other model, the mice develop metastatic mammary
tumors (23).
Targeted Mutations in Breast Cancer
Susceptibility Genes
Gene
targeted mice have been have been generated for all major breast cancer
susceptibility genes including BRCA1, BRCA2, p53,
PTEN, ATM, and APC. The study of gene-deficient mice
with different genetic backgrounds, alone or in combination with other
breast cancer susceptibility, modifier genes, or exposures may provide
information about the variables that influence or protect against breast
cancer development.
Women
who inherit mutation in the BRCA1 and BRCA2 breast cancer
susceptibly genes have up to an 85% chance of developing breast cancer
in their lifetimes. Numerous investigators have developed mice with
targeted mutation in these genes. The inheritance of a single mutated
copy of Brca1 or Brca2 does not increase the risk of mammary tumors
in mice. However, the exposure of mice heterozygous for the Brca1
or Brca2 gene to DES for 26 weeks, beginning a week before the
onset of ductal morphogenesis resulted in inhibited mammary branching
structure compared to the wild-type littermates at six months of age
(24).
Whereas
there are no published reports of viable Brca1-null mice, the
viability of Brca2 null mice depends on the position of the mutation
with more 3í alterations favoring survival. Mice with Brca2 mutations
within or immediately 3í of the BRC repeats occasionally survive and
succumb to thymic lymphoma at an early age (25,26). Brca2-null
mice lacking the terminal exon 27 are largely viable and are susceptible
to spontaneous tumor development (McAllister et al., manuscript
in preparation). In addition, the females display inhibited ductal morphology
in the mammary glands. Conditional Brca1-null mice have been
generated that inactivate Brca1 specifically in the mammary gland.
These mice display an inhibited ductal branching pattern and develop
mammary tumors after a year of age (27). Tumor progression is accelerated
by crossing these mice onto a p53 heterozygous genetic background.
These mouse models may provide a useful model for the study of prevention
strategies or therapeutics in high risk populations as well as the general
population.
Mutations
of the p53 tumor suppressor gene are the most common genetic
alteration in human cancer. Women in Li-Fraumini cancer families who
inherit mutation in the p53 gene are at increased risk of developing
breast cancer, and women and men display increased incidence of cancer
at multiple sites including soft tissue sarcomas, osteosarcomas and
lymphomas. Gene-targeting and homologous recombination were used to
develop mice homozygous for an exon 5 mutation (28). The homozygous
null p53 mice developed normally but are highly susceptible to neoplastic
development with a 74% tumor incidence by 6 months of age, yet mammary
tumors are rarely observed. Hemizygous p53 mice rarely develop tumors
before 9 months of age but the tumors that do develop are similar to
the spectrum observed in the p53 null mice and include lymphomas, soft
tissue sarcomas and osteosarcomas. When MMTV/Wnt-1 transgenic
mice, which develop mammary neoplasias, are crossed onto a p53-null
genetic background they develop mammary tumor at an accelerated rate
compared to those mice with a wild-type p53 genetic background.
This suggests that p53 defects can contribute to mammary carcinogenesis
in mice (29).
Adenomatous
polyposis coli (APC) is a tumor suppressor gene that when mutated
is involved in sporadic and inherited colon cancer and predisposes individuals
to the development of hundreds to thousands of colorectal polyps, a
subset of which can acquire the ability to progress to carcinomas (30,31).
Recent studies have investigated the association between the I1307K
APC allele and the development of breast cancer (32,33). The I1307K
polymorphism gives rise to an unstable (A)n in the coding
region which enhances the possibility of polymerase slippage during
DNA replication. Breast cancer patients who inherited the I1307K allele
were twice as likely to carry a mutation in BRCA1 or BRCA2
compared to controls. Thus, it has been suggested that the APC
gene may be a low penetrance breast cancer susceptibility gene or perhaps
a modifier of the BRCA loci (32,33).
Several
Apc mutant mouse models exist that are predisposed to spontaneous intestinal
tumors (34,35), similar to that which is observed in humans with inherited
APC mutations. The ApcMin mutant mice are
highly susceptible to the development of multiple intestinal neoplasms
and are susceptible to mammary tumor induction when treated with the
alkylating agent N-ethyl-N-nitrosourea (36-38). In another model,
Apc1638N mutant mice display an increase in intestinal tumor multiplicity
after irradiation as well as a 15-fold increase in mammary tumor incidence
(39). Thus, the mutant Apc genotype can confer high susceptibility
to both chemically- and radiation-induced mammary tumorigenesis. However,
mammary tumor susceptibility is not altered by Brca2 heterozygosity
in the ApcMin mouse model (40).
DMBA rat model of carcinogenesis
The
DMBA Sprague Dawley rat tumorigenesis model is a commonly used model
for not only understanding the effects of exposure during different
windows of mammary gland development but also to evaluate the potential
of agents to prevent tumor induction. Notable examples of the effect
of exposure during different stages of mammary gland development have
been demonstrated and several are described in the following paragraphs.
The
chemical exposure of rats in utero can influence mammary tumorigenesis
in the adult. The soy isoflavone genistein is a weak estrogen receptor
agonist, a tyrosine kinase and angiogenesis inhibitor, and an antioxidant
(41). Genistein administration to rats during gestation results in a
dose-dependent increase in mammary tumor susceptibility in the adult
animal (42). Exposure to the anti-estrogen tamoxifen during fetal development,
at days 15 and 20 gestation, increases mammary tumor susceptibility
in female offspring treated with DMBA at 45 days of age (42). The tumors
that developed in the tamoxifen exposed rats were less differentiated
and more aggressive than those in the non-tamoxifen exposed group. The
administration of TCDD, a toxic halogenated hydrocarbon, to rats during
gestation increases mammary tumor susceptibility in the adult animal
(43). Analysis of the ductal epithelium of the TCDD treated females
revealed that the mammary branching structure is less well developed
than the controls (43). This less complex mammary ductal branching pattern
is similar in morphology to an immature gland sensitive to DNA damaging
agents.
Although
TCDD mediates its effects through the Ah receptor, it can have effects
on endocrine end organs. TCDD exposure in the rat model clearly illustrates
that timing can be critical for carcinogen evaluation and may be relevant
to human exposure (43-45). The treatment of adult rats with TCDD inhibits
or delays DMBA-induced mammary tumors and can cause regression of existing
tumors (44,46). TCDD exposure inhibits ovulation by interfering with
follicular rupture and is consistent with the observation that loss
of ovarian function is protective for mammary cancers that occur in
an endocrine pathway (47).
The
window of mammary ductal development extending from birth to puberty
appears to be critical for the inhibitory effects of genistein against
mammary tumor development. Exposure to dietary genistein from birth
until sexual maturity confers dose-dependent protection to DMBA-induced
mammary cancer in rats (48). The ductal morphology of the mammary glands
isolated from these rats displayed accelerated mammary ductal epithelial
differentiation and correlated with protection against mammary tumor
development in the rat (48).
The
exposure of rats during or after sexual maturation can have very different
effects than earlier exposures. Various diets containing soy compounds
were fed to rats to identify components that might confer protection
to mammary tumor development. Rats were exposed to diets containing
or lacking combinations of isoflavones beginning at 42 weeks of age
and one week before DMBA treatment. Rats that began consuming diets
supplemented with the isoflavone daidzein, daidzein and genistein, or
depleted of both isoflavones developed significantly fewer mammary tumors,
but without reduced incidence, than the control group (49). In a similarly
designed study, a statistically significant difference in DMBA-induced
mammary tumor incidence, multiplicity, or latency was not detected among
rats fed soy protein, isoflavone-depleted soy protein, or control diets
(50). Similarly, Tamoxifen can inhibit tumor development in the mammary
glands of some rats exposed to DMBA or NMU (51).
Conclusion
Numerous
animal models exist in which to study mammary carcinogenesis including
transgenic rodents, gene-targeted mice, and inbred and outbred rodents.
The models are useful for asking questions about the many stages of
the carcinogenic process from initiation, through promotion to progression.
In addition, the whole animal permits the study of exposures during
the different stages of mammary gland growth and development which is
important because there is increasing focus on the timing of some exposures
as it relates to breast cancer susceptibility. While no one model will
provide all the answers about breast cancer, the study of models in
combination with in vitro studies should increase our understanding
of disease and enable us to translate some observations to the clinical
setting.
Progress
in the identification of risk factors, mechanism of action of environmental
exposures, and the consequences of genetic polymorphisms or mutations
will require a multidisciplinary approach. Information from animal models
in combination with epidemiology, computer modeling, and in vitro
studies will contribute to a greater understanding of human breast cancer
etiology. In turn, this complementary information that can be used to
develop science-based recommendations for reducing the risks of breast
cancer in humans.
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